Genetics of Muscular Dystrophies from Pathogenesis to Gene Therapy

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (20 November 2022) | Viewed by 28942

Special Issue Editors

Dipartimento di Scienze Mediche Traslazionali, Università degli Studi della Campania "Luigi Vanvitelli, 81100 Caserta CE, Italy
Interests: muscular dystrophies; dystrophinopathies; myotonic dystrophies; congenital muscular dystrophies; channelopathies; laminopathies; xchromosome inactivation; spinal muscular dystrophies; cardiomyopathires
IRCCS Fondazione Stella Maris, viale del Tirreno 331, 56128 Calambrone, Pisa, Italy
Interests: muscular dystrophies

Special Issue Information

Dear Colleagues, 

Background: Muscular dystrophies (MDs) are a clinically and genetically heterogeneous group of skeletal muscle diseases with progressive muscle weakness and atrophy. The severity and distribution of affected muscles can vary greatly in different forms and in single patients. This is in part due to the variety of genetic mutations that can cause the different MDs.

Aim and scope: This Special Issue will provide new insights in the field of muscular dystrophies, focusing on genetic background, genotype–phenotype correlations, novel therapeutic options driven by genetic characterization, and potential modifiers in MDs. We are also interested in manuscripts or learned reviews identifying genetic biomarkers in MDs and how these can define a more precise disease categorization.

History: The advent of new-generation sequencing has opened a new opportunity to unveil a larger set of MDs. The use of new techniques has also offered new tools to discover more precise genotype–phenotype correlations and revisit established MD classification based on clinical criteria only.

Cutting-edge research: Huge advances in basic research and a better understanding of the pathophysiology of these diseases have led to various molecular pipeline therapies for MDs. Within the last few years, promising new molecular therapies have been developed, facilitating causative therapy in the near future. New developments of personalized gene therapy target genetically defined disease subgroups of MDs, based on the underlying molecular mechanism and resulting phenotype. 

What kind of papers we are soliciting: Original articles and/or reviews. 

Dr. Luisa Politano
Dr. Filippo M. Santorelli
Guest Editors

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Keywords

  • muscular dystrophies
  • dystrophinopathies
  • myotonic dystrophies
  • congenital muscular dystrophies

Published Papers (11 papers)

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Editorial

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3 pages, 170 KiB  
Editorial
Editorial for the Genetics of Muscular Dystrophies from the Pathogenesis to Gene Therapy Special Issue
by Luisa Politano and Filippo M. Santorelli
Genes 2023, 14(4), 926; https://doi.org/10.3390/genes14040926 - 17 Apr 2023
Viewed by 926
Abstract
Muscular dystrophies (MDs) make up a clinically and genetically heterogeneous group of skeletal muscle diseases with progressive muscle weakness and atrophy [...] Full article
(This article belongs to the Special Issue Genetics of Muscular Dystrophies from Pathogenesis to Gene Therapy)

Research

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22 pages, 10709 KiB  
Article
Genetic Analysis of HIBM Myopathy-Specific GNE V727M Hotspot Mutation Identifies a Novel COL6A3 Allied Gene Signature That Is Also Deregulated in Multiple Neuromuscular Diseases and Myopathies
by Shivangi Attri, Moien Lone, Amit Katiyar, Vikas Sharma, Vinay Kumar, Chaitenya Verma and Suresh Kumar Gahlawat
Genes 2023, 14(3), 567; https://doi.org/10.3390/genes14030567 - 24 Feb 2023
Cited by 2 | Viewed by 1631
Abstract
The GNE-associated V727M mutation is one of the most prevalent ethnic founder mutations in the Asian HIBM cohort; however, its role in inducing disease phenotype remains largely elusive. In this study, the function of this hotspot mutation was profoundly investigated. For this, V727M [...] Read more.
The GNE-associated V727M mutation is one of the most prevalent ethnic founder mutations in the Asian HIBM cohort; however, its role in inducing disease phenotype remains largely elusive. In this study, the function of this hotspot mutation was profoundly investigated. For this, V727M mutation-specific altered expression profile and potential networks were explored. The relevant muscular disorder-specific in vivo studies and patient data were further analyzed, and the key altered molecular pathways were identified. Our study found that the GNEV727M mutation resulted in a deregulated lincRNA profile, the majority of which (91%) were associated with a down-regulation trend. Further, in silico analysis of associated targets showed their active role in regulating Wnt, TGF-β, and apoptotic signaling. Interestingly, COL6a3 was found as a key target of these lincRNAs. Further, GSEA analysis showed HIBM patients with variable COL6A3 transcript levels have significant alteration in many critical pathways, including epithelial-mesenchymal-transition, myogenesis, and apoptotic signaling. Interestingly, 12 of the COL6A3 coexpressed genes also showed a similar altered expression profile in HIBM. A similar altered trend in COL6A3 and coexpressed genes were found in in vivo HIBM disease models as well as in multiple other skeletal disorders. Thus, the COL6A3-specific 13 gene signature seems to be altered in multiple muscular disorders. Such deregulation could play a pivotal role in regulating many critical processes such as extracellular matrix organization, cell adhesion, and skeletal muscle development. Thus, investigating this novel COL6A3-specific 13 gene signature provides valuable information for understanding the molecular cause of HIBM and may also pave the way for better diagnosis and effective therapeutic strategies for many muscular disorders. Full article
(This article belongs to the Special Issue Genetics of Muscular Dystrophies from Pathogenesis to Gene Therapy)
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14 pages, 2015 KiB  
Article
Using Cluster Analysis to Overcome the Limits of Traditional Phenotype–Genotype Correlations: The Example of RYR1-Related Myopathies
by Claudia Dosi, Anna Rubegni, Jacopo Baldacci, Daniele Galatolo, Stefano Doccini, Guja Astrea, Angela Berardinelli, Claudio Bruno, Giorgia Bruno, Giacomo Pietro Comi, Maria Alice Donati, Maria Teresa Dotti, Massimiliano Filosto, Chiara Fiorillo, Fabio Giannini, Gian Luigi Gigli, Marina Grandis, Diego Lopergolo, Francesca Magri, Maria Antonietta Maioli, Alessandro Malandrini, Roberto Massa, Sabrina Matà, Federico Melani, Sonia Messina, Andrea Mignarri, Maurizio Moggio, Elena Maria Pennisi, Elena Pegoraro, Giulia Ricci, Michele Sacchini, Angelo Schenone, Simone Sampaolo, Monica Sciacco, Gabriele Siciliano, Giorgio Tasca, Paola Tonin, Rossella Tupler, Mariarosaria Valente, Nila Volpi, Denise Cassandrini and Filippo Maria Santorelliadd Show full author list remove Hide full author list
Genes 2023, 14(2), 298; https://doi.org/10.3390/genes14020298 - 23 Jan 2023
Cited by 5 | Viewed by 2942
Abstract
Thanks to advances in gene sequencing, RYR1-related myopathy (RYR1-RM) is now known to manifest itself in vastly heterogeneous forms, whose clinical interpretation is, therefore, highly challenging. We set out to develop a novel unsupervised cluster analysis method in a large patient population. [...] Read more.
Thanks to advances in gene sequencing, RYR1-related myopathy (RYR1-RM) is now known to manifest itself in vastly heterogeneous forms, whose clinical interpretation is, therefore, highly challenging. We set out to develop a novel unsupervised cluster analysis method in a large patient population. The objective was to analyze the main RYR1-related characteristics to identify distinctive features of RYR1-RM and, thus, offer more precise genotype–phenotype correlations in a group of potentially life-threatening disorders. We studied 600 patients presenting with a suspicion of inherited myopathy, who were investigated using next-generation sequencing. Among them, 73 index cases harbored variants in RYR1. In an attempt to group genetic variants and fully exploit information derived from genetic, morphological, and clinical datasets, we performed unsupervised cluster analysis in 64 probands carrying monoallelic variants. Most of the 73 patients with positive molecular diagnoses were clinically asymptomatic or pauci-symptomatic. Multimodal integration of clinical and histological data, performed using a non-metric multi-dimensional scaling analysis with k-means clustering, grouped the 64 patients into 4 clusters with distinctive patterns of clinical and morphological findings. In addressing the need for more specific genotype–phenotype correlations, we found clustering to overcome the limits of the “single-dimension” paradigm traditionally used to describe genotype–phenotype relationships. Full article
(This article belongs to the Special Issue Genetics of Muscular Dystrophies from Pathogenesis to Gene Therapy)
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18 pages, 2558 KiB  
Article
Spectrum of Genetic Variants in the Dystrophin Gene: A Single Centre Retrospective Analysis of 750 Duchenne and Becker Patients from Southern Italy
by Emanuela Viggiano, Esther Picillo, Luigia Passamano, Maria Elena Onore, Giulio Piluso, Marianna Scutifero, Annalaura Torella, Vincenzo Nigro and Luisa Politano
Genes 2023, 14(1), 214; https://doi.org/10.3390/genes14010214 - 14 Jan 2023
Cited by 6 | Viewed by 2275
Abstract
Dystrophinopathies are X-linked recessive muscle disorders caused by mutations in the dystrophin (DMD) gene that include deletions, duplications, and point mutations. Correct diagnosis is important for providing adequate patient care and family planning, especially at this time when mutation-specific therapies are [...] Read more.
Dystrophinopathies are X-linked recessive muscle disorders caused by mutations in the dystrophin (DMD) gene that include deletions, duplications, and point mutations. Correct diagnosis is important for providing adequate patient care and family planning, especially at this time when mutation-specific therapies are available. We report a large single-centre study on the spectrum of DMD gene variants observed in 750 patients analyzed for suspected Duchenne (DMD) or Becker (BMD) muscular dystrophy, over the past 30 years, at the Cardiomyology and Medical Genetics of the University of Campania. We found 534 (71.21%) large deletions, 73 (9.73%) large duplications, and 112 (14.93%) point mutations, of which 44 (5.9%) were small ins/del causing frame-shifts, 57 (7.6%) nonsense mutations, 8 (1.1%) splice site and 3 (0.4%) intronic mutations, and 31 (4.13%) non mutations. Moreover, we report the prevalence of the different types of mutations in patients with DMD and BMD according to their decade of birth, from 1930 to 2020, and correlate the data to the different techniques used over the years. In the most recent decades, we observed an apparent increase in the prevalence of point mutations, probably due to the use of Next-Generation Sequencing (NGS). In conclusion, in southern Italy, deletions are the most frequent variation observed in DMD and BMD patients followed by point mutations and duplications, as elsewhere in the world. NGS was useful to identify point mutations in cases of strong suspicion of DMD/BMD negative on deletions/duplications analyses. In the era of personalized medicine and availability of new causative therapies, a collective effort is necessary to enable DMD and BMD patients to have timely genetic diagnoses and avoid late implementation of standard of care and late initiation of appropriate treatment. Full article
(This article belongs to the Special Issue Genetics of Muscular Dystrophies from Pathogenesis to Gene Therapy)
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10 pages, 963 KiB  
Communication
Miyoshi Muscular Dystrophy Type 1 with Mutated DYSF Gene Misdiagnosed as Becker Muscular Dystrophy: A Case Report and Literature Review
by Joonhong Park, Young Jae Moon and Dal Sik Kim
Genes 2023, 14(1), 200; https://doi.org/10.3390/genes14010200 - 12 Jan 2023
Cited by 3 | Viewed by 1636
Abstract
Dysferlinopathy covers a spectrum of muscle disorder categorized by two major phenotypes, namely Miyoshi muscular dystrophy type 1 (MMD1, OMIM #254130) and limb-girdle muscular dystrophy autosomal recessive 2 (LGMDR2, OMIM #253601), and two minor symptoms, including asymptomatic hyperCKemia and distal myopathy with anterior [...] Read more.
Dysferlinopathy covers a spectrum of muscle disorder categorized by two major phenotypes, namely Miyoshi muscular dystrophy type 1 (MMD1, OMIM #254130) and limb-girdle muscular dystrophy autosomal recessive 2 (LGMDR2, OMIM #253601), and two minor symptoms, including asymptomatic hyperCKemia and distal myopathy with anterior tibial onset (DMAT, OMIM #606768). We report the first Korean MMD1 misdiagnosed as Becker muscular dystrophy (BMD), which was caused by a combination of compound heterozygous c.663 + 1G > C and p.Trp992Arg of the DYSF gene. A 70-year-old male previously diagnosed with BMD was admitted for genetic counseling. Since he was clinically suspected to have dysferlinopathy but not BMD, targeted panel sequencing was performed to discover the potential hereditary cause of the suspected muscular dystrophy in the proband. Consequently, two pathogenic single nucleotide variants of the DYSF gene, c.663 + 1G > C (rs398123800) and p.Trp992Arg (rs750028300), associated with dysferlinopathy were identified. These variants were previously reported with variant allele frequencies of 0.000455 (c.663 + 1G > C) and 0.000455 (c.2974T > C; p.Trp992Arg) in the Korean population. This report emphasizes the need for common variant screening in the diagnostic algorithms of certain muscle disorders or gene panels with potential pathogenic effects and high rates of recurrent variants. Full article
(This article belongs to the Special Issue Genetics of Muscular Dystrophies from Pathogenesis to Gene Therapy)
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10 pages, 1864 KiB  
Article
Intergenerational Influence of Gender and the DM1 Phenotype of the Transmitting Parent in Korean Myotonic Dystrophy Type 1
by Ji Yoon Han, Woori Jang and Joonhong Park
Genes 2022, 13(8), 1465; https://doi.org/10.3390/genes13081465 - 17 Aug 2022
Cited by 1 | Viewed by 1426
Abstract
Myotonic dystrophy type 1 (DM1) is the most common autosomal-dominant disorder caused by the CTG repeat expansion of the DMPK, and it has been categorized into three phenotypes: mild, classic, and congenital DM1. Here, we reviewed the intergenerational influence of gender and [...] Read more.
Myotonic dystrophy type 1 (DM1) is the most common autosomal-dominant disorder caused by the CTG repeat expansion of the DMPK, and it has been categorized into three phenotypes: mild, classic, and congenital DM1. Here, we reviewed the intergenerational influence of gender and phenotype of the transmitting parent on the occurrence of Korean DM1. A total of 44 parent–child pairs matched for the gender of the transmitting parent and the affected child and 29 parent–child pairs matched for the gender and DM1 phenotype of the transmitting parent were reviewed. The CTG repeat size of the DMPK in the affected child was found to be significantly greater when transmitted by a female parent to a female child (DM1-FF) (median, 1309 repeats; range, 400–2083) than when transmitted by a male parent to a male child (650; 160–1030; p = 0.038 and 0.048 using the Tukey HSD and the Bonferroni test) or by a male parent to a female child (480; 94–1140; p = 0.003). The difference in the CTG repeat size of the DMPK between the transmitting parent and the affected child was also lower when transmitted from a male parent with classic DM1 (−235; −280 to 0) compared to when it was transmitted from a female parent with mild DM1 (866; 612–905; p = 0.015 and 0.019) or from a female parent with classic DM1 (DM1-FC) (605; 10–1393; p = 0.005). This study highlights that gender and the DM1 phenotype of the transmitting parent had an impact on the CTG repeat size of the DMPK in the affected child, with greater increases being inherited from the DM1-FF or DM1-FC situations in Korean DM1. Full article
(This article belongs to the Special Issue Genetics of Muscular Dystrophies from Pathogenesis to Gene Therapy)
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13 pages, 1865 KiB  
Article
Central Core Disease: Facial Weakness Differentiating Biallelic from Monoallelic Forms
by Ana Cotta, Lucas Santos Souza, Elmano Carvalho, Leticia Nogueira Feitosa, Antonio Cunha, Jr., Monica Machado Navarro, Jaquelin Valicek, Miriam Melo Menezes, Simone Vilela Nunes Neves, Rafael Xavier-Neto, Antonio Pedro Vargas, Reinaldo Issao Takata, Julia Filardi Paim and Mariz Vainzof
Genes 2022, 13(5), 760; https://doi.org/10.3390/genes13050760 - 26 Apr 2022
Cited by 2 | Viewed by 1901
Abstract
Central Core Disease (CCD) is a genetic neuromuscular disorder characterized by the presence of cores in muscle biopsy. The inheritance has been described as predominantly autosomal dominant (AD), and the disease may present as severe neonatal or mild adult forms. Here we report [...] Read more.
Central Core Disease (CCD) is a genetic neuromuscular disorder characterized by the presence of cores in muscle biopsy. The inheritance has been described as predominantly autosomal dominant (AD), and the disease may present as severe neonatal or mild adult forms. Here we report clinical and molecular data on a large cohort of Brazilian CCD patients, including a retrospective clinical analysis and molecular screening for RYR1 variants using Next-Generation Sequencing (NGS). We analyzed 27 patients from 19 unrelated families: four families (11 patients) with autosomal dominant inheritance (AD), two families (3 patients) with autosomal recessive (AR), and 13 sporadic cases. Biallelic RYR1 variants were found in six families (two AR and four sporadic cases) of the 14 molecularly analyzed families (~43%), suggesting a higher frequency of AR inheritance than expected. None of these cases presented a severe phenotype. Facial weakness was more common in biallelic than in monoallelic patients (p = 0.0043) and might be a marker for AR forms. NGS is highly effective for the identification of RYR1 variants in CCD patients, allowing the discovery of a higher proportion of AR cases with biallelic mutations. These data have important implications for the genetic counseling of the families. Full article
(This article belongs to the Special Issue Genetics of Muscular Dystrophies from Pathogenesis to Gene Therapy)
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Review

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14 pages, 10577 KiB  
Review
GDP-Mannose Pyrophosphorylase B (GMPPB)-Related Disorders
by Pitcha Chompoopong and Margherita Milone
Genes 2023, 14(2), 372; https://doi.org/10.3390/genes14020372 - 31 Jan 2023
Cited by 6 | Viewed by 2148
Abstract
GDP-mannose pyrophosphorylase B (GMPPB) is a cytoplasmic protein that catalyzes the formation of GDP-mannose. Impaired GMPPB function reduces the amount of GDP-mannose available for the O-mannosylation of α-dystroglycan (α-DG) and ultimately leads to disruptions of the link between α-DG and extracellular proteins, hence [...] Read more.
GDP-mannose pyrophosphorylase B (GMPPB) is a cytoplasmic protein that catalyzes the formation of GDP-mannose. Impaired GMPPB function reduces the amount of GDP-mannose available for the O-mannosylation of α-dystroglycan (α-DG) and ultimately leads to disruptions of the link between α-DG and extracellular proteins, hence dystroglycanopathy. GMPPB-related disorders are inherited in an autosomal recessive manner and caused by mutations in either a homozygous or compound heterozygous state. The clinical spectrum of GMPPB-related disorders spans from severe congenital muscular dystrophy (CMD) with brain and eye abnormalities to mild forms of limb-girdle muscular dystrophy (LGMD) to recurrent rhabdomyolysis without overt muscle weakness. GMPPB mutations can also lead to the defect of neuromuscular transmission and congenital myasthenic syndrome due to altered glycosylation of the acetylcholine receptor subunits and other synaptic proteins. Such impairment of neuromuscular transmission is a unique feature of GMPPB-related disorders among dystroglycanopathies. LGMD is the most common phenotypic presentation, characterized by predominant proximal weakness involving lower more than upper limbs. Facial, ocular, bulbar, and respiratory muscles are largely spared. Some patients demonstrate fluctuating fatigable weakness suggesting neuromuscular junction involvement. Patients with CMD phenotype often also have structural brain defects, intellectual disability, epilepsy, and ophthalmic abnormalities. Creatine kinase levels are typically elevated, ranging from 2 to >50 times the upper limit of normal. Involvement of the neuromuscular junction is demonstrated by the decrement in the compound muscle action potential amplitude on low-frequency (2–3 Hz) repetitive nerve stimulation in proximal muscles but not in facial muscles. Muscle biopsies typically show myopathic changes with variable degrees of reduced α-DG expression. Higher mobility of β-DG on Western blotting represents a specific feature of GMPPB-related disorders, distinguishing it from other α-dystroglycanopathies. Patients with clinical and electrophysiologic features of neuromuscular transmission defect can respond to acetylcholinesterase inhibitors alone or combined with 3,4 diaminopyridine or salbutamol. Full article
(This article belongs to the Special Issue Genetics of Muscular Dystrophies from Pathogenesis to Gene Therapy)
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13 pages, 1822 KiB  
Review
Anoctamin 5 (ANO5) Muscle Disorders: A Narrative Review
by Pannathat Soontrapa and Teerin Liewluck
Genes 2022, 13(10), 1736; https://doi.org/10.3390/genes13101736 - 27 Sep 2022
Cited by 5 | Viewed by 3912
Abstract
Anoctaminopathy-5 refers to a group of hereditary skeletal muscle or bone disorders due to mutations in the anoctamin 5 (ANO5)-encoding gene, ANO5. ANO5 is a 913-amino acid protein of the anoctamin family that functions predominantly in phospholipid scrambling and plays a key [...] Read more.
Anoctaminopathy-5 refers to a group of hereditary skeletal muscle or bone disorders due to mutations in the anoctamin 5 (ANO5)-encoding gene, ANO5. ANO5 is a 913-amino acid protein of the anoctamin family that functions predominantly in phospholipid scrambling and plays a key role in the sarcolemmal repairing process. Monoallelic mutations in ANO5 give rise to an autosomal dominant skeletal dysplastic syndrome (gnathodiaphyseal dysplasia or GDD), while its biallelic mutations underlie a continuum of four autosomal recessive muscle phenotypes: (1). limb–girdle muscular dystrophy type R12 (LGMDR12); (2). Miyoshi distal myopathy type 3 (MMD3); (3). metabolic myopathy-like (pseudometabolic) phenotype; (4). asymptomatic hyperCKemia. ANO5 muscle disorders are rare, but their prevalence is relatively high in northern European populations because of the founder mutation c.191dupA. Weakness is generally asymmetric and begins in proximal muscles in LGMDR12 and in distal muscles in MMD3. Patients with the pseudometabolic or asymptomatic hyperCKemia phenotype have no weakness, but conversion to the LGMDR12 or MMD3 phenotype may occur as the disease progresses. There is no clear genotype–phenotype correlation. Muscle biopsy displays a broad spectrum of pathology, ranging from normal to severe dystrophic changes. Intramuscular interstitial amyloid deposits are observed in approximately half of the patients. Symptomatic and supportive strategies remain the mainstay of treatment. The recent development of animal models of ANO5 muscle diseases could help achieve a better understanding of their underlying pathomechanisms and provide an invaluable resource for therapeutic discovery. Full article
(This article belongs to the Special Issue Genetics of Muscular Dystrophies from Pathogenesis to Gene Therapy)
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11 pages, 429 KiB  
Review
Current Outline of Exon Skipping Trials in Duchenne Muscular Dystrophy
by Gökçe Eser and Haluk Topaloğlu
Genes 2022, 13(7), 1241; https://doi.org/10.3390/genes13071241 - 14 Jul 2022
Cited by 15 | Viewed by 4993
Abstract
Molecular treatments for Duchenne muscular dystrophy (DMD) are already in clinical practice. One particular means is exon skipping, an approach which has more than 15 years of background. There are several promising clinical trials based on earlier works. The aim is to be [...] Read more.
Molecular treatments for Duchenne muscular dystrophy (DMD) are already in clinical practice. One particular means is exon skipping, an approach which has more than 15 years of background. There are several promising clinical trials based on earlier works. The aim is to be able to initiate the production of enough dystrophin to change the rate of progression and create a clinical shift towards the better. Some of these molecules already have received at least conditional approval by health authorities; however, we still need new accumulating data. Full article
(This article belongs to the Special Issue Genetics of Muscular Dystrophies from Pathogenesis to Gene Therapy)
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Other

7 pages, 1823 KiB  
Case Report
The First Russian Patient with Native American Myopathy
by Aysylu Murtazina, Nina Demina, Polina Chausova, Olga Shchagina, Artem Borovikov and Elena Dadali
Genes 2022, 13(2), 341; https://doi.org/10.3390/genes13020341 - 13 Feb 2022
Cited by 4 | Viewed by 4065
Abstract
Congenital myopathy associated with pathogenic variants in the STAC3 gene has long been considered native American myopathy (NAM). In 2017, the first case of a non-Amerindian patient with this myopathy was described. Here, we report the first Russian patient with NAM. The patient [...] Read more.
Congenital myopathy associated with pathogenic variants in the STAC3 gene has long been considered native American myopathy (NAM). In 2017, the first case of a non-Amerindian patient with this myopathy was described. Here, we report the first Russian patient with NAM. The patient is a 17-year-old female with compound-heterozygous single nucleotide variants in the STAC3 gene: c.862A>T, p.(Lys288Ter) and c.93del, p.(Lys32ArgfsTer78). She has a milder phenotype than the earlier described patients. To our knowledge, this is the first case of a patient who had both nonsense and frameshift variants. It is assumed that the frameshift variant with premature stop codon lead to nonsense-mediated RNA decay. However, there are two additional coding isoforms of the STAC3 gene, which are not affected by this frameshift variant. We can speculate that these isoforms may partially carry out the function, and possibly explain the milder phenotype of our patient. Full article
(This article belongs to the Special Issue Genetics of Muscular Dystrophies from Pathogenesis to Gene Therapy)
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